Anthracycline induced Cardiomyopathy

Anthracycline induced Cardiomyopathy

AM Report

December 11 2009AM Report

December 11 2009

Chemotherapy and Cardiotoxicity

Chemotherapy and Cardiotoxicity

Anthracyclines Herceptin Antimetabolites

5-fluorouracil - coronary vasospasm Fludarabine - high dose for BMT conditioning

Vinca alkaloids - hypertension, myocardial ischemia Taxanes - conduction abnormalities Cyclophosphamide - cardiomyopathy Bleomycin - pericarditis Mitomycin C - heart failure Monoclonal antibodies

Anthracyclines Herceptin Antimetabolites

5-fluorouracil - coronary vasospasm Fludarabine - high dose for BMT conditioning

Vinca alkaloids - hypertension, myocardial ischemia Taxanes - conduction abnormalities Cyclophosphamide - cardiomyopathy Bleomycin - pericarditis Mitomycin C - heart failure Monoclonal antibodies

History of Anthracycline useHistory of Anthracycline use

Fermentation product of Streptomyces peucetius

Daunomycin and doxorubicin devolped in 1960s

Clinical Uses breast and esophageal

carcinomas osteosarcoma, Kaposi's sarcoma and soft-

tissue sarcomas Hodgkin's and non-

Hodgkin's lymphomas

Fermentation product of Streptomyces peucetius

Daunomycin and doxorubicin devolped in 1960s

Clinical Uses breast and esophageal

carcinomas osteosarcoma, Kaposi's sarcoma and soft-

tissue sarcomas Hodgkin's and non-

Hodgkin's lymphomas Doxorubicin

MechanismMechanism

Therapuetic Intercalating between base

pairs of the DNA/RNA Inhibits topoiosomerase II

enzyme

Cardiotoxicity Production of toxic oxygenﾊ free radicals and an increase in oxidative stress

Loss of myofibrils and the vacuolization of cytoplasm

Therapuetic Intercalating between base

pairs of the DNA/RNA Inhibits topoiosomerase II

enzyme

Cardiotoxicity Production of toxic oxygenﾊ free radicals and an increase in oxidative stress

Loss of myofibrils and the vacuolization of cytoplasm

Risk Factors - Cumulative doseRisk Factors - Cumulative dose

0

20

40

60

80

100

Inc

ide

nc

e o

f C

HF

(%

)

< 350 550 600 700Cumulative Dose (mg/m2)

Incidence of CHF as a Function of Cumulative Doxorubicin Dose

0

20

40

60

80

100

Inc

ide

nc

e o

f C

HF

(%

)

< 350 550 600 700Cumulative Dose (mg/m2)

Incidence of CHF as a Function of Cumulative Doxorubicin Dose

Risk FactorsRisk Factors

Age <3 years of age and >70 years of age

Previous/Concurrent Radiation Concomitant chemotherapy

Herceptin and taxols Bone Marrow Transplant Cardiac Risk Factors

Age <3 years of age and >70 years of age

Previous/Concurrent Radiation Concomitant chemotherapy

Herceptin and taxols Bone Marrow Transplant Cardiac Risk Factors

Clinical ManifestationsClinical Manifestations

Acute - during infusion to 1 week Arrhythmias Ventricular dysfunction Pericarditis/myocarditis

Early - < 1 year Dose-related cardomyopathy

Late

Acute - during infusion to 1 week Arrhythmias Ventricular dysfunction Pericarditis/myocarditis

Early - < 1 year Dose-related cardomyopathy

Late

MonitoringMonitoring

Serial noninvasive monitoring of LVEF Radionuclide angiography (MUGA) Echocardiography

Exercise stress radionuclide ventriculography Biomarkers

Serum troponins BNP/pro-BNP

Endomyocardial Biopsy

Serial noninvasive monitoring of LVEF Radionuclide angiography (MUGA) Echocardiography

Exercise stress radionuclide ventriculography Biomarkers

Serum troponins BNP/pro-BNP

Endomyocardial Biopsy

MonitoringMonitoring

Normal EF Baseline (prior to 100 mg/m2) 2nd study after 250 to 300 mg/m2 3rd at 400-450 mg/m2 Sequential studies prior to each additional dose

EF 30-50% EF study prior to each dose

EF < 30% - recommend against initiating Discontinue doxorubicin for decrease in EF

>10% or absolute < 30%

Normal EF Baseline (prior to 100 mg/m2) 2nd study after 250 to 300 mg/m2 3rd at 400-450 mg/m2 Sequential studies prior to each additional dose

EF 30-50% EF study prior to each dose

EF < 30% - recommend against initiating Discontinue doxorubicin for decrease in EF

>10% or absolute < 30%

PreventionPrevention

Altering infusion protocol Alternate anthracycline derivatives Liposomal preparations Dexrazoxane - metal-chelating agent Beta-blockers ACE inhibitors

Altering infusion protocol Alternate anthracycline derivatives Liposomal preparations Dexrazoxane - metal-chelating agent Beta-blockers ACE inhibitors

Prognosis and TreatmentPrognosis and Treatment

Prognosis Mortality rates of > 30% in early studies

Treatment ACE inhibitors Traditional Heart failure Management Heart Transplant

Prognosis Mortality rates of > 30% in early studies

Treatment ACE inhibitors Traditional Heart failure Management Heart Transplant

RefrencesRefrences

Up-to-Date Cancer Medicine 6 CHEST February 1999 vol. 115 no. 2 569-571 Schwartz, RG, McKenzie, WB, Alexander, J, et al. Congestive heart

failure and left ventricular dysfunction complication doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med 1987; 82:1109.

Jannazzo A, Hoffman J, Lutz M. Monitoring of anthracycline-induced cardiotoxicity. Ann Pharmacother. 2008 Jan;42(1):99-104.

Appel JM, Nielsen D, Zerahn B, Jensen BV, Skagen K. Anthracycline-induced chronic cardiotoxicity and heart failure. Acta Oncol. 2007;46(5):576-80.

Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998 Sep 24;339(13):900-5.

Up-to-Date Cancer Medicine 6 CHEST February 1999 vol. 115 no. 2 569-571 Schwartz, RG, McKenzie, WB, Alexander, J, et al. Congestive heart

failure and left ventricular dysfunction complication doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med 1987; 82:1109.

Jannazzo A, Hoffman J, Lutz M. Monitoring of anthracycline-induced cardiotoxicity. Ann Pharmacother. 2008 Jan;42(1):99-104.

Appel JM, Nielsen D, Zerahn B, Jensen BV, Skagen K. Anthracycline-induced chronic cardiotoxicity and heart failure. Acta Oncol. 2007;46(5):576-80.

Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998 Sep 24;339(13):900-5.